APOE genotype is the strongest genetic risk factor for late-onset Alzheimer?s disease (AD) with apoE4 increasing risk and apoE2 decreasing risk. In addition to apoE?s strong effects on A? clearance and aggregation, it has other effects that are important in how it may influence AD pathogenesis in an isoform- dependent fashion. We found that either lowering apoE or removing apoE/A? complexes in APP/PS1- 21;human apoE knockin (KI) mice produces beneficial effects in mouse models of A? deposition or tauopathy. Lowering apoE levels with anti-sense oligonucleotides (ASOs) early in life decreased A? deposition. When lowered after A? seeding had occurred, it did not lower A? deposition but it significantly decreased the amount of A?-induced neuritic dystrophy. In a mouse model of primary tauopathy (P301S Tau Tg mice), apoE4 markedly increased tau-mediated neurodegeneration, and both brain atrophy and the innate immune response were blocked in P301S mice lacking apoE. The data suggest that apoE is exacerbating the brain?s innate immune response in the setting of neural damage to worsen injury. Recently, we found that Trem2, an apoE receptor on microglia, strongly inhibits A?-induced neuritic tau seeding and spreading. To further understand whether targeting apoE should be in some way move forward therapeutically as well as further define whether its effects are Trem2-dependent, we propose to utilize models where 1) we have evidence that apoE is driving tau-mediated neurodegeneration and 2) a model in which A? pathology and tau seeding/spreading occur in a fashion that mimics types of A? and tau AD pathology seen in human AD. We hypothesize that apoE, in an isoform-dependent fashion, influences A?-mediated tau seeding/spreading and tau-mediated neurodegeneration in a TREM2-dependent fashion and that therapeutically reducing apoE levels in the adult CNS will attenuate amyloid-induced damage to neurons, amyloid-induced tau seeding/spreading, and tau-induced neurodegeneration. We propose these aims. Aim 1. To determine whether lowering apoE levels either before or after the onset of tau pathology with ASOs or via over-expression of the low density lipoprotein receptor (LDLR) decreases neurodegeneration, synaptic loss, the innate immune response, and improves function in P301S;apoE KI mice. We will also decrease human TREM2 with ASOs or activate it with agonizing TREM2 antibodies in P301S;apoE KI mice also expressing human TREM2. Aim 2: To determine the effects of targeting apoE by lowering apoE levels either before or after the onset of human AD-tau seeding with ASOs targeting apoE, by administering an antibody to non-lipidated apoE, or via over-expression of LDLR in APPNL-F ;E2, APPNL-F ;E3, and APPNL-F ;E4 mice. Aim 3: We will utilize a mouse neuronal/mixed glial culture system to assess the effects of apoE isoforms on tau-mediated neurodegeneration and determine 1) whether secreted apoE is responsible for the effects on tau-mediated neurodegeneration and 2) whether TREM2 is required for the effects of apoE and is either upstream or downstream of apoE.